Efficacy, Safety and Immunogenicity Evaluation of MTBVAC in Newborns in Sub-Saharan Africa

NCT04975178 | Recruiting Phase 3 DMC

• 1 other identifier: MTBVACN3
• Study Type: interventional
• Target: 7,120
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this project is to demonstrate safety, immunogenicity and improved efficacy of the new live attenuated M. tuberculosis vaccine called MTBVAC in a Phase 3 efficacy trial in HIV-uninfected infants born to HIV-infected and HIV-uninfected mothers as compared to standard of care BCG vaccination. The proposal builds upon a group of TB vaccine development partners in Europe and sub-Saharan Africa established in a previous EDCTP-supported project. It creates an expanded consortium of clinical trial partners for the optimal implementation of a large infant efficacy trial of MTBVAC in high TB incidence settings. New capacity for efficacy trials in infants will be a valuable resource for the TB vaccine development community. The proposal will create a network of institutions in three TB endemic African countries with enhanced laboratory capacity to conduct TB vaccine immunology studies and to bio-bank samples to discover immune correlates of vaccine-mediated protection.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• To demonstrate efficacy in terms of incidence of MTBVAC against TB disease in healthy HU and HEU newborns compared to BCG

  Primary: Time from vaccination to diagnosis of first confirmed or unconfirmed TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB disease from day of vaccination. Secondary: Confirmed TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB from day of vaccination. Exploratory: i) Time from vaccination to diagnosis of first unconfirmed or unlikely TB disease, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB disease from day of vaccination. ii) Confirmed or unconfirmed TB, which might be right-censored due to loss to follow-up, death, or successful completion of the study without acquiring TB carried out with a washout period of 90 days after vaccination. iii) Confirmed TB disease; iv) Unconfirmed or unlikely TB disease (ver ii for iii and iv).

  Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Secondary Outcomes (1)

• To assess the safety and reactogenicity of MTBVAC in healthy HU and HEU newborns compared to BCG.

  Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Other Outcomes (5)

• Tertiary objective: To assess immunogenicity of MTBVAC in healthy HU and HEU newborns.

  Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

• Exploratory objective: To assess immunogenicity of MTBVAC in healthy HU and HEU newborns.

  Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

• Exploratory objective: To biobank samples for (future) biomarker studies to identify immunological correlates of vaccine-induced protection and biomarkers of risk for TB disease

  Minimum of 24 months to a maximum 80 months; or until study end in South Africa.

Study Arms (2)

MTBVAC

EXPERIMENTAL

Both MTBVAC and BCG vaccines are administered by intradermal route in the left deltoid region. One 0.05 mL reconstituted dose of MTBVAC will be defined based on the phase IIa results. MTBVAC is manufactured by Biofabri. MTBVAC is formulated (1.5 - 8.5 x104 CFU/dose, 1.5 - 8.5 x105 CFU/dose or 1.5 - 8.5 x106 CFU/dose (to be selected) and presented as a lyophilised pellet in 20 dose vials (0.05 mL/dose, after reconstitution with sterile water for injection). MTBVAC vaccine will be released and distributed by BIOFABRI, and imported to the sites following approval by the local regulatory authority. MTBVAC vaccine must be stored at +2°C to +8°C. Reconstituted MTBVAC vaccine must be stored at +2ºC to +8ºC and administered as soon as possible, within 4 hours of reconstitution. A single vaccine vial will be used for each participant.

Biological: MTBVAC

BCG

ACTIVE COMPARATOR

BCG is a live attenuated M. bovis strain developed 100 years ago and is used as a preventive vaccine against tuberculosis. It is administered at birth. One 0.05 mL reconstituted dose of BCG contains 2.5 x 105 CFU. The control vaccine will be the BCG vaccine available and recommended in South Africa at time of the trial. BCG vaccine produced by AJ Biologics (formerly Staten Serum Institute) is the only BCG vaccine (Danish strain) currently licensed for routine use in South Africa. The recommended BCG injection volume for newborn infants (0.05 mL, after reconstitution with BCG diluent) contains approximately 2.5 x 105 CFU (range 1-4 x 105 CFU). BCG vaccine vials should be stored in the site pharmacy at 2-8ºC.

Biological: BCG

Interventions

MTBVAC BIOLOGICAL

MTBVAC is a novel TB vaccine candidate based on an attenuated M. tuberculosis clinical isolate of the Euro-American lineage. Attenuation is based on two independent, stable genetic deletions of the genes phoP and fadD26 coding for two major virulence factors, the transcription factor PhoP and the cell-wall lipids PDIM, respectively. We hypothesize that MTBVAC will provide improved protection, as individuals latently infected with live M.tuberculosis have an 80% lower chance of developing TB, and as MTBVAC contains most of the genes deleted from BCG and presents a wider collection of antigens to the host immune system. Preclinical studies in different animal models indicated that MTBVAC is safe and is able to induce an improved protection compared to BCG.

MTBVAC

BCG BIOLOGICAL

BCG is a live attenuated M. bovis strain developed 100 years ago and is used as a preventive vaccine against tuberculosis. It is administered at birth.

BCG

Eligibility Criteria

• Age: 5 Minutes - 7 Days
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Male or female newborns within seven days of birth.
• Written informed maternal consent, including permission to access maternal antenatal, postnatal, and infant medical records.
• Infant participants and their caregivers available for trial follow-up and display the willingness and capacity to comply with trial procedures.
• Newborns must be in good general health during pregnancy and delivery, as assessed by medical history and targeted physical examination.
• Birth weight ≥ 2450 grams.
• Apgar score at 5 minutes ≥ 7.
• A maternal HIV test result (rapid test, enzyme-linked immunosorbent assay (ELISA), or Polymerase chain reaction (PCR)) taken within 30 days of delivery, or within seven days post-partum must be available and documented if HIV uninfected. If the mother is HIV infected, then she must be on antiretroviral (ARV) therapy as per in-country guidelines with a viral load of \<50 copies/mL (within six months of labour).
• Estimated gestational age ≥ 37 weeks.
• Mother has not participated in a clinical trial within three months prior to the infant's birth.
• Mother has never participated in a TB vaccine trial before.
• Infant may not participate in any other clinical trials.

You may not qualify if:

• Receipt of BCG vaccination prior to enrolment.
• Significant antenatal, intrapartum, or postpartum complications that may affect the health of the newborn.
• Skin condition, bruising or birth mark at the intended injection site.
• Maternal HIV test (rapid test, ELISA, or PCR) result not available.
• HIV exposed Newborn's HIV PCR result positive or not available.
• Maternal history of TB during pregnancy.
• History of close/household contact with a TB patient, antenatal or postnatal, whether maternal, other family member or another household member who has not yet completed TB treatment.
• Clinically suspected neonatal sepsis.
• Any severe congenital malformation.

Sponsors & Collaborators

• Biofabri, S.L: lead
• TuBerculosis Vaccine Initiative: collaborator
• University of Cape Town: collaborator
• Institut Pasteur de Madagascar: collaborator
• Biomedical Research Center EPLS: collaborator
• Universidad de Zaragoza: collaborator
• University of Stellenbosch: collaborator
• University of KwaZulu: collaborator
• Wits Health Consortium (Pty) Ltd: collaborator

Study Sites (1)

South African Tuberculosis Initiative, Brewelskloof Hospital

Worcester, Western Cape, 6850, South Africa

RECRUITING

Related Publications (21)

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Related Links

• WHO, Global Tuberculosis Report 2022. \[Online\] https://www.who.int/publications /i/item/9789240061729 \[accessed on 27 June 2023\].
• WHO preferred products characteristics for TB vaccines 2018. \[Online\] https://apps.who.int/iris/ bitstream/handle/10665/273089/ WHO-IVB-18.06-eng.pdf?ua=1 \[accessed on 05 May 2021\].
• Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017. \[Online\] https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables \[Accessed on 05 May 2021\].

MeSH Terms

Conditions

Tuberculosis

Interventions

MTBVAC vaccine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Mark Hatherill

  University of Cape Town, Faculty of Health Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ingrid Murillo Jelsbak

CONTACT

+34 986 33 04 00; ingrid.murillo@biofabri.es

Andrea García Silva

CONTACT

+34 986 33 04 00; a.garciasilva@biofabri.es

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: MTBVAC and BCG vaccine will be prepared, and allocation concealed by the site pharmacist. All other site staff will be blinded to vaccine allocation, throughout the follow-up period. Data pertaining to the MTBVAC vaccine and to BCG control will be collected in an observer-blinded manner. Blinding will be maintained throughout the vaccination and follow-up portions of the vaccine trial. No set of individual codes will be held at Biofabri's Headquarters. Biofabri's Headquarters will be able to access the individual randomization code from the SATVI Pharmacy randomization register. The code will be broken by the Site's Pharmacist (Study Contact for Emergency Code Break) only in the case of medical events that the investigator/physician in charge of the participant feels cannot be treated without knowing the identity of the study vaccine(s). The Site's Pharmacist is responsible for unblinding the treatment assignment in accordance with specified time frames for expedited reporting of SAEs.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study is designed to include the following: 1. Safety population (all study participants randomized to receive BCG or MTBVAC in a 1:1 fashion): All participants from the 4 South African sites (approx. 7000); all 120 participants from Madagascar \& Senegal. 2. Reactogenicity population: \- First 1000 from the 4 South African sites and all 120 in Madagascar and Senegal. 3. Immunogenicity population (subset of the safety population - total 460): \- First 60 HU and 25 HEU participants from the South African sites (total 340) and all 120 from Madagascar \& Senegal. 4. Efficacy population (subset of the safety population - all participants from the South African sites): * First 1000, including 240 HU and 100 HEU newborns. * Additional 6000 (not part of reactogenicity \& immunogenicity population). Senegal \& Madagascar participants are excluded from the efficacy population. DSMB will periodically review cumulative safety and reactogenicity data.

Study Record Dates

• First Submitted: June 21, 2021
• First Posted: July 23, 2021
• Study Start: October 17, 2022
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): February 1, 2029
• Last Updated: February 10, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)